Poly-4-hydroxybutyrate (P4HB) and copolymers thereof can be produced using transgenic fermentation methods, see, for example, U.S. Pat. No. 6,548,569 to Williams et al., and are produced commercially, for example, by Tepha, Inc. (Lexington, Mass.). Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is a strong, pliable thermoplastic polyester that, despite its biosynthetic route, has a relatively simple structure as shown in FIG. 1.
The polymer belongs to a larger class of materials called polyhydroxyalkanoates (PHAs) that are produced by numerous microorganisms (see, for example, Steinbüchel., et al., FEMS Microbial. Lett. 128:219-228 (1995)). In nature these polyesters are produced as storage granules inside cells, and serve to regulate energy metabolism. They are also of commercial interest because of their thermoplastic properties, biodegradability and relative ease of production.
Chemical synthesis of P4HB has been attempted, but it has been impossible to produce the polymer with a sufficiently high molecular weight that is necessary for most applications (see Hori, Y., et al., Polymer 36:4703-4705 (1995); Houk, et al., J. Org. Chem., 2008, 73 (7), 2674-2678; and Moore, T., et al., Biomaterials 26:3771-3782 (2005)). In fact, it has been calculated to be thermodynamically impossible to chemically synthesize a high molecular weight homopolymer under normal conditions (Moore, et al., Biomaterials 26:3771-3782 (2005)).
U.S. Pat. Nos. 6,245,537, 6,623,748, 7,244,442, and 8,231,889 describe methods of making PHAs with little to no endotoxin, which are suitable for medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493, 6,867,247, 7,268,205, 7,179,883, 7,268,205, 7,553,923, 7,618,448 and 7,641,825 and WO 2012/064526 describe use of PHAs to make medical devices. Copolymers of P4HB include 4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid (U.S. Pat. No. 8,039,237 to Martin and Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No. 6,323,010 to Skraly et al.). Methods to control molecular weight of PHA polymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.
PHAs with controlled degradation and degradation in vivo of less than one year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764, 6,828,357, 6,867,248, and 6,878,758 to Williams et al. and WO 99/32536 to Martin et al. Applications of P4HB have been reviewed in Williams, S. F., et al., Polyesters, III, 4:91-127 (2002), and by Martin, et al., Biochem. Eng. J. 16:97-105 (2003). Medical devices and applications of P4HB have also been disclosed by WO 00/56376 to Williams et al. Several patents including U.S. Pat. Nos. 6,555,123, 6,585,994, and 7,025,980 describe the use of PHAs in tissue repair and engineering. U.S. Pat. Nos. 8,034,270, 8,016,883, 8,287,909, WO 2011/119742 and WO 2011/159784 disclose fibers, non-wovens, and textiles made by melt extrusion of P4HB.
Several patent applications including WO 98/51812 to Williams, WO 99/32536 to Martin, WO 00/56376 to Williams mention that PHAs may be injection molded. Certain patents describe injection molding of PHAs containing 3-hydroxyacids, including the homopolymer, poly-3-hydroxybutyrate (P3HB also known as PHB), and copolymers of 3-hydroxybutyrate with 3-hydroxyvalerate (PHBV) and copolymers with 4-hydroxybutyrate. Notably, U.S. Pat. No. 5,061,743 to Herring discloses the difficulties in processing PHAs containing 3-hydroxyacids, such as PHB and PHBV, due to their low crystallization rates, and the need to reduce cycle times. PHB also has a very narrow thermal processing window that can result in thermal decomposition of the polymer processed at elevated temperatures. Herring accordingly discloses additives such as organophosphonic acids and metal oxides to enable the injection molding of PHAs containing 3-hydroxyacids. Notably, Herring and others do not disclose how to injection mold P4HB, or how P4HB could be injection molded without additives. Moreover, since PHB and P4HB have entirely different physical and chemical properties, disclosures describing conditions to injection mold PHB do not teach how to injection mold P4HB. For example, PHB has a melt temperature of 180° C., and therefore a different thermal profile is necessary to injection mold P4HB, which has a melt temperature of just 60° C. PHB and P4HB also do not share the same molecular structure, and therefore have different crystallization rates, and whereas PHB is a relatively brittle material, P4HB is a strong pliable and tough thermoplastic.
WO 2005/007195 to Hasirci discloses a solution method to mold rods of P4HB, but does not disclose injection molded rods of P4HB. WO 2007/092418 to Schmitz discloses blends of P4HB with PLLA, and mentions that these blends may be injection molded to make tubes for stent application. In this invention, the P4HB is used to toughen PLLA. Schmitz does not disclose injection molding of P4HB or conditions to injection mold blends of P4HB with PLLA (poly-L-lactic acid). WO 2007/092417 to Rizk also discloses blends of P4HB with PLLA, wherein the P4HB is used to toughen PLLA, but does not disclose conditions to injection mold these blends or the P4HB homopolymer.
Thus, there is no disclosure of how P4HB can be injection molded, the intrinsic viscosities of P4HB that can be processed by injection molding, the loss of intrinsic viscosity upon injection molding P4HB, the conditions necessary to injection mold P4HB, the properties of P4HB moldings, such as tensile strength, elongation to break, bending strength, and tensile modulus, produced by injection molding, or the benefits of injection molding P4HB.
It is therefore an object of the present invention to provide compositions of P4HB that can be injection molded.
It is another object of the present invention to provide a means of injection molding P4HB.
It is a further object of the present invention to provide moldings of P4HB produced by injection molding characterized by specific physical properties.
It is still another object of the present invention to provide moldings of P4HB produced by injection molding with enhanced mechanical properties and controlled degradation profiles that can be used in medical applications.